High total cholesterol may signal protective factor ... or survival bias

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Cognitively-intact people ages 85 to 94 years old whose total cholesterol had increased since around age 40 had a 32% reduced risk for marked cognitive decline over the next 10 years, according to data from the longitudinal Framingham Heart Study.

Note that these results demonstrate that some relationships of cholesterol and other risk factors with subsequent marked cognitive decline diminish, or even reverse, as outcome age increases.

Elderly people whose total cholesterol increased from midlife to age 85 may have a reduced risk for marked cognitive decline, an observational study of the longitudinal Framingham Heart Study cohort suggested.

Cognitively intact people aged 85 to 94 years old whose total cholesterol had increased since around age 40 had a 32% reduced risk for marked cognitive decline over the next 10 years, reported Jeremy Silverman, PhD, and James Schmeidler, PhD, of Icahn School of Medicine at Mount Sinai in New York City.

In contrast, people ages 75 to 84 whose cholesterol was elevated had a 50% increased risk, they wrote online in Alzheimer's & Dementia.

"There have been many studies that looked at total cholesterol as a risk factor for dementia and Alzheimer's disease," Silverman said. "And many have found that it is indeed a risk factor. But most of those studies looked at relatively young elderly people -- people who were followed up when they were in their late 60s up to their mid 70s."

"We studied people who are very old, particularly people who continue to stay cognitively healthy up into late old age," he told MedPage Today. "Looking at the Framingham Heart study allowed us to see there is a difference in the association between cholesterol and cognitive decline. As one reached older and older ages, particularly after age 85, high cholesterol at midlife was associated with a better cognitive outcome than having normal cholesterol at midlife."

This phenomenon is not new, commented Sujuan Gao, PhD, of Indiana University School of Medicine in Indianapolis, who was not involved with the study. "The APOE ε4 allele, a known genetic risk factor for Alzheimer's disease, was shown to have reduced or no effect in the oldest old population," she said. "BMI, another risk factor for cardiovascular disease, has also been shown to have no association with coronary artery disease, or even be protective in old age."

"These are often attributed to the so-called survivor effects -- those who survive to the oldest old, despite of carrying risk genes or exposed to risk factors, may have other protective factors not yet discovered," Gao told MedPage Today.

For this study, Silverman and Schmeidler used data from the original Framingham Heart Study -- a long-term, ongoing cardiovascular cohort study that began in 1948 -- to study the association of total cholesterol with cognitive decline in five comparisons: total cholesterol at midlife (average age 40) and late-life (average age 77), average cholesterol since midlife, and linear and quadratic changes in measures of cholesterol.

They studied 1,897 participants who had intact cognition when they entered the Framingham Heart Study. The average age at entry was 40, and about 61% of the sample was female.

The researchers defined marked cognitive decline as a Mini–Mental State Examination (MMSE) score ≤20, and intact cognition as MMSE ≥25. They considered total cholesterol under 200 mg/dL normal, while anything above that was deemed high.

Several values -- including high last cholesterol and increasing cholesterol levels -- were associated with increased risk of a marked cognitive decline. But as the outcome age increased, some associations diminished or reversed.

In the subgroup of cognitively healthy 85 to 94 year olds, the fall in linear slope was significant and showed that a high midlife cholesterol level was associated with a reduced risk for marked cognitive decline.

Statin use was associated with some protection against marked cognitive decline, but its effect diminished with advancing age. At age 85 and above, statins did not appear to confer any additional protection.

These results might reflect a protected survivor model, Silverman observed. In this type of model, an individual's underlying risk does not change as his or her age increases, but the people who are more vulnerable have greater attrition than the protected minority of people who survive. If this model applies, the oldest-old participants are likely to have other protective factors for successful cognitive aging that can be tested in future studies, he added.

Other limitations of the study included that it looked only at total cholesterol, not low or high density lipoprotein cholesterol, and did not include other cardiovascular risk factors or general measures of frailty. The statin use covariate also was not relevant in the early years of the Framingham study, although subsidiary analyses that excluded statin users did not significantly change the major findings.

This study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

The researchers reported no conflicts of interest pertaining to this report.

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